tbuckley/cabot-search huggingface dataset:
PB1920: CLINICOHEMATOLIGICAL CHARACTERISTICS AND CYTOGENETIC PROFILE OF CHRONIC MYELOMONOCYTIC LEUKEMIA; AN EXPERIENCE FROM PAKISTAN
Authors: N. ANWAR, Z. ZIAD, N. FATIMA, A. KHALID, L. MAJEED, M. BORHANY
Journal: HemaSphere (2022)

Background: Chronic myelomonocytic Leukemia (CMML) is a clonal stem cell disorder characterized by the presence of sustained (>3 months) peripheral blood monocytosis (≥1 x 109/L; monocytes ≥10% of white blood cell count) along with dysplastic features in the blood/bone marrow. The pathophysiology of CMML is very complex and heterogenous demonstrating overlapping features of myelodysplasia and proliferation. Aims: The aim of the study was to study baseline clinicohematological characteristics, and cytogenetics profile of this disorder in our population Methods: A cross sectional study was conducted at National Institute of Blood Diseases and Bone Marrow Transplantation, Karachi Pakistan from 2018-2021. Approval from the Institutional ethics committee was obtained prior to the study. Baseline investigations were done and clinical parameters were recorded. Bone marrow biopsy samples were taken and stained by leishman’s stain. Cytogenetic analysis was performed on overnight, 24-h un-stimulated and 72-h stimulated bone marrow cultures using standard procedures. Descriptive statistics were reported by using SPSS version 23.0 Results: A total of 18 patients were included in the study having median age 63(28-85) years with male predominance 11(61%). Out of total, 15(83%) had no addiction and 12 (67%) were from lower socioeconomic status. Out of 18, 6(33%) had known comorbids, 5(28%) had hepatomegaly, and 11(61%) had splenomegaly. Symptoms at presentation included fever 10(56%), weight loss 9(50%), shortness of breath in 8(44%), bleeding and gastrointestinal discomfort in 3(17%) respectively. The duration of symptoms before presentation was 8 (2-192) weeks. Transfusion dependent anemia at presentation was found in 14(78%) of patients. Out of 18, 16(89%) had normal karyotype. Median (range) hemoglobin (g/dl), platelet countx109/L, total leucocyte count x109/, monocytes x109/ and blast (%) was 9.3(5.7-14.2), 2(2-249), 35.2(3.4-145.8), 6.5(1.3-26.1) and 6(1-19) respectively. Out of total, 10 (56%) were alive, 2(11%) were expired and 6 (33%) were lost to follow up at the time of study analysis. Summary/Conclusion: This was one of the first studies conducted on CMML Pakistani patients. The range duration of symptoms before presentation was found much longer which might represent delayed referrals. Routine follow ups and clinical treatment data would be important addition to the existing data done prospectively. Further longitudinal studies with inferential statistics are needed in this context.
PB2075: CRYSTAL STORING HISTIOCYTOSIS PRESENTING AS HEAD AND NECK TUMORS
Authors: E. P. De La Flor Weiss, A. Tupac-Yupanqui
Journal: HemaSphere (2022)

Background: Crystal storing histiocytosis (CSH) is a benign proliferation of histiocytes ladden with crystals of immunoglobulin, usually containing kappa light chain in association with a clonal lymphoplasmacytic disorder. Clinical manifestations of CSH may overshadow the underlying lymphoproliferation, usually an indolent lymphoma. Diagnosis is made by tissue examination in the proper clinical, imaging, and serologic context. Aims: This report highlights the importance of considering the diagnosis of CSH in the differential of H&N lesions to reach the diagnosis with additional sytemic evaluation to establish extent of involvement for both CSH and lymphoma. In addition, we emphasize that persistence of CSH mass lesions does not imply failure of lymphoma treatment. Methods: Clinical features, imaging, and pathology are reviewed in three patients who presented with head and neck masses: palate mucosa, tonsil, and lacrimal gland respectively. Preliminary pathologic diagnosis was oncocytic neoplasia or histiocytosis NOS in two cases. The third patient was initially diagnosed as CSH. Further testing including Ig levels and molecular studies were also diagnostic and contributory for monitoring of disease status and response to therapy. Results: Additional clinical hematology/hematopathology evaluation including bone marrow examination (figure 1) revealed systemic involvement by low grade lymphoma as well as involvement of bone marrow and lymph nodes with CSH. One patient had been diagnosed with Myd88 negative Waldentrom’s lymphoplasmacytic lymphoma 9 years earlier and treated with anti Cd20 and radiation therapy with apparent good response and remained asymptomatic until two months before presenting with tonsil mass Current evaluation disclosed a similar lymphoma with Myd88 negative clone and CSH. Image:Summary/Conclusion: Initial diagnostic evaluation of oncocyte-like histiocytic lesions of H&N, however benign or bland in appearance, raise the differential of lymphoma and CSH, and require additional work-up and perhaps systemic evaluation, including bone marrow examination. Lack or decrease in size/volume of CSH lesions after treatment for lymphoma does not indicate failure of therapy but requires alternate monitoring criteria.
The Interaction of SWI/SNF with the Ribosome Regulates Translation and Confers Sensitivity to Translation Pathway Inhibitors in Cancers with Complex Perturbations
Authors: Livia Ulicna, Samuel C. Kimmey, Christopher M. Weber, Grace M. Allard, Aihui Wang, Nam Q. Bui, Sean C. Bendall, Gerald R. Crabtree, Gregory R. Bean, Capucine Van Rechem
Journal: Cancer Research (2022)

Abstract Subunits from the chromatin remodelers mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) are mutated, deleted, or amplified in more than 40% of cancers. Understanding their functions in normal cells and the consequences of cancerous alterations will provide insight into developing new targeted therapies. Here we examined whether mSWI/SNF mutations increase cellular sensitivity to specific drugs. Taking advantage of the DepMap studies, we demonstrate that cancer cells harboring mutations of specific mSWI/SNF subunits exhibit a genetic dependency on translation factors and are sensitive to translation pathway inhibitors. Furthermore, mSWI/SNF subunits were present in the cytoplasm and interacted with the translation initiation machinery, and short-term inhibition and depletion of specific subunits decreased global translation, implicating a direct role for these factors in translation. Depletion of specific mSWI/SNF subunits also increased sensitivity to mTOR-PI3K inhibitors. In patient-derived breast cancer samples, mSWI/SNF subunits expression in both the nucleus and the cytoplasm was substantially altered. In conclusion, an unexpected cytoplasmic role for mSWI/SNF complexes in translation suggests potential new therapeutic opportunities for patients afflicted by cancers demonstrating alterations in their subunits. Significance: This work establishes direct functions for mSWI/SNF in translation and demonstrates that alterations in mSWI/SNF confer a therapeutic vulnerability to translation pathway inhibitors in cancer cells.
PB1839: INDEPENDENT PROGNOSTIC VALUE OF A PLATELET COUNT OVER 300X109/L IN ACUTE MYELOBLASTIC LEUKEMIA PATIENTS TREATED WITH AN INTENSIVE REGIMEN.
Authors: I. Ródenas Quiñonero, A. Jeréz, B. Ferrer, E. Orna, J. T. Navarro-Ferrando, J. M. Raya, T. Martin-Santos, M. Ricard, A. Bermejo, R. Morales, C. Prats, M. Navarrete, V. Roldán-Galiacho, M. L. Amigo, V. Vicente, F. J. Ortuño
Journal: HemaSphere (2022)

Background: Acute myeloblastic leukemia (AML) usually presents with cytopenias, although its degree is variable and in some cases it is non-existent. We herein highlight the existence of “de novo” AML patients that debut with a normal or elevated platelet count. Aims: Our aim was to evaluate the prognostic impact of a platelet count over >300 x109/L at diagnosis. Methods: One hundred and twenty-eight adult patients from nine tertiary centers of Spain, with a diagnostic of non-promyelocytic AML between 2000 and 2021, were included. Two groups were defined based on platelet count at diagnosis: those who debuted with a platelet count over >300 x109/L and those who debuted with a lower platelet count. Patients were also distributed in two different groups according to whether they received intensive chemotherapy treatment. We used the Kaplan-Meier and the Cox method to analyze overall survival (OS), with a two-sided P value ≤ 0.15 for a factor in the univariate analysis to be included in the multivariate regression, where a P value ≤ 0.05 was considered statistically significant. Statistical analysis was performed using SPSS software (IBM SPSS Statistics 21, IBM Corporation, Chicago, IL). Results: A total of 128 patients were included. The median age at diagnosis was 65 y.o (25-89). Eighty patients (62.5%) had received an intensive regimen. Patients were considered upon platelet count: higher or less than 300 x109/L. We found significant differences in the white blood cells (WBC) count (19.9x109/L vs 5.3x109/L, p= 0.047), the percentage of patients who responded to treatment and in those who achieved complete remission, (56.0% vs 87.0%, p=0.004 and 44 .0% vs 80.4%, p=0.002, respectively). Figure 1 shows how presenting a platelet count over 300 x109/L was an adverse prognostic factor only in the group that received an intensive regimen. Within this group, only the age (p=0.079), the blast count (%) in bone marrow (p=0.05) and belong to intermediate-adverse European LeukemiaNet-2017 (ELN2017) risk group (p=0.008), were significantly associated with a shorter OS in the univariate analysis When confronting these variables with the presence of a platelet count at diagnosis over 300x109/L, only intermediate-adverse ELN2017 risk group and the platelet count remained significant for a shorted OS (p=0,023, HR 2.17, 95%CI 1.11-4.24 and p=0.025, HR 3.50, 95% CI 1.16-10.54, for platelet count and ELN risk group, respectively). Image:Summary/Conclusion: In “de novo” AML patients treated with an intensive regimen, an unusually high platelet count is related to a worse prognosis. In those patients, a specific molecular study focused on megakaryopoiesis could be of interest.
PB1887: NETWORK META-ANALYSIS OF PROGRESSION FREE SURVIVAL IN THE TREATMENT OF RELAPSED OR REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA
Authors: A. Chanan-Khan, T. Liu, K. Yang, A. Cohen, K. Fahrbach, J. Campbell, B. Tang
Journal: HemaSphere (2022)

Background: Zanubrutinib, a next-generation Bruton’s tyrosine kinase inhibitor (BTKi), demonstrated superior overall response rate and a trend toward improved progression-free survival (PFS) as compared to ibrutinib in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) in the phase 3 ALPINE trial (NCT03734016) based on interim analysis. However, its comparative efficacy with other treatments is not known. Aims: The goal of this study was to estimate the relative efficacy of zanubrutinib compared with standard treatments for R/R CLL through a network meta-analysis (NMA). Methods: The efficacy of zanubrutinib from ALPINE (study of zanubrutinib and ibrutinib in patients with R/R CLL was compared to ibrutinib, acalabrutinib, bendamustine and rituximab (BR), and venetoclax + rituximab using data from 4 RCTs. Relevant RCTs were identified using a systematic literature review. A network was constructed that composed RCTs (ALPINE, ELEVATE-RR [NCT02477696], ASCEND [NCT02970318], and MURANO [NCT02005471]). Bayesian network meta-analysis (NMA) models were used to simultaneously synthesize hazard ratios (HRs) and 95% credible intervals (CrIs) for investigator-assessed PFS and overall survival (OS) to estimate the relative efficacy of zanubrutinib versus comparators of interest. An assumption of constant hazard ratio was applied in the NMA analysis. Analyses were performed using well-established codes published by the National Institute for Health and Care Excellence (NICE) Decision Support Unit and were implemented with OpenBUGS (version 3.2.3). Results: The NMA suggested a significant improvement in PFS for zanubrutinib over acalabrutinib (HR = 0.52, 95% CrI [0.30, 0.90]), ibrutinib (0.47, [0.29, 0.76]), and BR (0.13, [0.06, 0.26]). Zanubrutinib had a numerically better PFS than venetoclax + rituximab (0.69, [0.32, 1.46]) while not reaching statistical significance. For OS, NMA results showed a trend favoring zanubrutinib over acalabrutinib (0.75, [0.35, 1.59]), ibrutinib (0.62, [0.31, 1.22]), and BR (0.52, [0.21, 1.24]). The difference was not statistically significant with wide CrIs, suggesting a high uncertainty as inherent limitation of the analysis. Image:Summary/Conclusion: This NMA reports the first summary of comparative PFS of available treatments for R/R CLL. Indirect treatment comparisons suggest PFS on zanubrutinib may be superior to other BTKis and immunochemotherapies in R/R CLL patients.
PB2201: THYMUS DEVELOPMENT IN CONGENITAL HEART DISEASES
Authors: I. Bódi, D. Belina, Z. Prodan, A. Škrtić, D. Heckel, D. Grčević, M. Antica
Journal: HemaSphere (2022)

Background: Congenital alterations of thymic development or thymectomy have a clear immunological impact on T cell development and function. The current thymus reconstitution strategies are based on enhancing the endogenous thymus regeneration or transplantation of thymic tissue, thymic epithelial pluripotent cells or thymic organoids. Most of the work relies on thymic tissue removed during cardiac surgery to provide access to the heart and major cardiac vessels. Although, these samples were considered healthy thymic tissues, we recently captured an interesting new phenotype of the thymus tissue in children with atrial septal defect (ASD). The thymic endodermal epithelial cells develop from the third pharyngeal pouches, induced by signalling network from the mesenchymal cells, which have neural crest origin. Aims: During thymus development the Foxn1 transcription factor is crucial for the development, function, and maintenance of the mature thymus. Foxn-1 influences the migration of neural crest-derived cells, their differentiation into mesenchymal cells, the transformation process in which they become fibroblasts of the capsule, septae and several cells in the medulla. The presence of neural crest cells is substantial in the functional development of the thymic anlage to take place to the epithelio-mesenchymal interactions. In the absence of neural crest cells, the epithelio-mesenchymal interaction is obstructed and therefore epithelial cells develop abnormally. We hypothesize that the septal defect is caused by the defective regulation of signalling processes in the neural crest cells, which can also influence thymus development. We aimed to dissect expression of crucial regulatory and signalling factors in thymus tissue samples and interpret them in the context of known healthy thymus characteristics. Methods: Immunohistochemistry, Confocal microscopy and 3D cell cultures Results: We compared EPCAM, FOXN1, DLL1 and cytokeratin expression by immunohistochemistry in the thymic tissue we recovered as medical waste from children with different congenital cardiac diseases. We found a clear cell compartment differences between the thymi recovered from surgery that so far were considered as healthy, especially in FOXN1 expression and TEC marker eypression. Image:Summary/Conclusion: Our results shed new light on human thymus development and regeneration possibilities from thymic epithelial precursor cells. By this research, we can get closer to understanding, recognizing and treating diseases as a result of immunodeficiency.
P1547: ACTIVATE-KIDS: MITAPIVAT IN CHILDREN WITH PYRUVATE KINASE DEFICIENCY WHO ARE NOT REGULARLY TRANSFUSED
Authors: R. F. Grace, P. D. Tyler, M. Little, P. A. Kosinski, V. Beynon
Journal: HemaSphere (2022)

Background: Pyruvate kinase (PK) deficiency is a rare, inherited disorder caused by PKLR gene mutations that is associated with chronic hemolytic anemia and lifelong complications. Clinical management includes red blood cell (RBC) transfusions and splenectomy, which only partially improves anemia. No pharmacotherapies are approved for use in children, and therapies targeting the underlying cause of hemolysis are needed. Mitapivat (AG-348), a first-in-class, oral, allosteric activator of the RBC PK enzyme, demonstrated significant and durable improvements in hemoglobin (Hb) and markers of hemolysis, hematopoiesis, and iron metabolism in adults with PK deficiency who were not regularly transfused (ACTIVATE NCT03548220, long-term extension study NCT03853798). Safety and efficacy data support the evaluation of mitapivat in children with PK deficiency who are not regularly transfused. Aims: Report the design of ACTIVATE-Kids (NCT05175105), a phase 3 study, which will evaluate the efficacy and safety of mitapivat in children with PK deficiency who are not regularly transfused. Methods: ACTIVATE-Kids, a global, multicenter, double-blind, placebo-controlled study, will stratify 30 children by age (1 to <6, 6 to <12, and 12 to <18 years); a minimum of 6 patients in each age group will be randomized (2:1) to mitapivat or placebo. The double-blind period comprises an 8-week dose-titration period and a 12-week fixed-dose period. A 5-year open-label period will follow the double-blind period. The study drug will be dosed (1–50 mg twice daily) according to patient age and weight, based on pharmacokinetic modeling data of adults with PK deficiency. Key inclusion criteria: ≥2 PKLR mutant alleles with ≥1 missense mutation, ≤5 RBC transfusions in the past year, Hb concentrations of ≤10 g/dL (12 to <18 years) or ≤9 g/dL (1 to <12 years). Key exclusion criteria: R479H homozygosity, 2 non-missense mutations without a missense mutation in PKLR, or prior stem cell transplantation. The primary endpoint is Hb response, defined as a ≥1.5 g/dL increase in Hb concentration from baseline that is sustained at ≥2 scheduled assessments at Weeks 12, 16, and 20 in the double-blind period. Secondary endpoints will evaluate the effect of mitapivat on Hb, hemolysis, erythropoiesis, iron metabolism and overload, safety, quality of life, and pharmacokinetics. Results: Global site recruitment is in-progress; an update on recruitment and patient enrollment will be provided. Summary/Conclusion: The phase 3 ACTIVATE-Kids study of children with PK deficiency who are not regularly transfused will evaluate treatment with mitapivat, a potential disease-modifying pharmacotherapy.
PB2128: CELL OF ORIGIN ACCORDING TO HANS LOGARITHM IS AN INDEPENDENT RISK FACTOR FOR DLBCL PATIENTS TREATED WITH R-CHOP: A REAL WORLD MOROCCAN EXPERIENCE
Authors: E. M. Mahtat, I. Ait Filali, M. Allaoui, S. Jennane, H. El Maaroufi, M. Oukabli, K. Doghmi
Journal: HemaSphere (2022)

Background: Diffuse large B cell lymphoma is classified into two molecular prognostic subgroups: germinal center B cell like (GCB) and activated B cell like (ABC), based on cell of origin (COO). The Hans algorithm based on immunohistochemistry (IHC) analysis helps classifying DLBCL into GCB and non-GCB subtypes in clinical practice. The non-GCB subtype has been correlated with inferior overall survival in the pre-rituximab era. The use of chemoimmunotherapy has shown variable results. Aims: We compared retrospectively the outcomes of DLBCL patients treated with R-CHOP in our center according to the COO. Methods: We retrospectively reviewed patients diagnosed with DLBCL and treated with R-CHOP from January 2010 to December 2020. Only patients with the COO obtained according to the Hans alborithm were include in the analysis. Demographic, prognostic and therapeutic data were collected. Overall survival (OS) and progression free survival (PFS) were estimated by the Kaplan-Meier method and compared by the log rank test. The COX model was used for the multivariate analysis. Results: A total of 140 patients with DLBCL treated with R-CHOP were analysed. Sixty-one had their COO identified by IHC. Median age was 58 years. 72% were male. 43 (70%) had advanced stage. According to Hans algorithm, 19 (31%) GCB origin, 42 (68%) were non-GCB. The median OS and PFS time were not reached for the total population. The OS wasn’t reached for the GCB and was estimated at 42 months for the non-GCB (p=0.039).The median progression free survival time was 24 months for non-GCB and not reached for GCB (p=0.049).When adjusted for other prognostic scores (IPI, R-IPI, NCCN-IPI, CNS-IPI) the GCB sub-type was significantly associated with longer OS HR=3,7 (95% CI, 1,03 -13,3) and PFS, HR=3,7 (95% CI, 1,13 - 12,1). Summary/Conclusion: In our local DLBCL population treated with immunochemotherapy the COO according to the Hans algorithm, despite the small number, was suprinsingly found to be a significant independent prognostic factor. This should be confirmed in future prospective studies in our region.
PB2264: A REVIEW OF MORPHOLOGICAL ABNORMALITIES ON PERIPHERAL BLOOD FILM: BEYOND ROUTINE ANALYSIS IN THE COVID-19 POPULATION IN THE FIRST WAVE OF THE DISEASE.
Authors: H. Fernandez Leyva
Journal: HemaSphere (2022)

Background: Vaccination is considered the most promising approach for ending or containing the coronavirus disease 2019 (COVID-19) pandemic. Available vaccines have proven highly safe and effective. The morphology appearance of the blood film is an excellent tool to analyse the disease severity. In late February of 2021, a prothrombotic syndrome was observed in a small number of individuals who received the ChAdOx1 CoV-19 vaccine (AstraZeneca, University of Oxford, and Serum Institute of India), an adenoviral vector-based vaccine. This syndrome has been designated vaccine-induced immune thrombotic thrombocytopenia (VITT) with a particular and intriguing characteristic. Aims: An examination of peripheral blood smear findings in COVID-19 patients was performed in 50 consecutive patients at the first wave of the disease and prior to the full vaccination program instituted with current-acute respiratory syndrome coronavirus 2 (SARS-CoV-2) confirmed disease (PCR)- Pneumonia Methods: A morphology analysis was aimed at identifying the principal abnormalities in patients diagnosed with COVID-19. Interestingly (but not surprisingly) the most severe forms were associated with a more prominent abnormalities, including leukoerythorblastic features and secondary hemophagocytic lymphohistiocytosis, leading to an often fatal outcomes. In this study, absolute lymphopenia (despite non constant) were the predominant feature despite its not specific to COVID-19. A spectrum of variant lymphocytes is seen in COVID-19 cases, albeit constituting less than 1% prolymphocytes in most cases. Plasmacytoid lymphocytes were more common as well as acquired Pelger-Huët were significantly observed (but not representative). Results: A laboratory findings reported in association with COVID-19 included leukopenia, lymphopenia, monocytosis, neutrophilia, eosinopenia, These abnormalities mainly highlight the severe, transitory and reversible perturbation of myelopoiesis, especially in the form of accelerated and disordered granulopoiesis, in patients with COVID19 in severe symptomatic phase. The hypothesis of quantitative and qualitative abnormalities can be related to the cytokine storm and hyperinflammation, which is a pathogenic factor in the evolution of COVID19 pneumonia. Summary/Conclusion: An early identification of severe lymphoid abnormality could represent a high risk factor for poor outcomes with COVID-19. A decreased number of mature lymphocytes, and eosinophils in peripheral blood smear were observed in the severe stage patients (p <0.05). The limitation of the study is in the small numbers of the analysed population and the absent of the control comparative group. The subsequent analysis after patient received at least two dose of the vaccination shows a less severe lymphopenia (P< 0.05) and disease severity